A 6-year follow-up of a large European cohort of children with attention-deficit/hyperactivity disorder-combined subtype: outcomes in late adolescence and young adulthood.

There are very few studies on the long-term outcome of children and adolescents with ADHD-combined type in Europe. The objective of the present study is to assess the 6-year outcome (including pharmacological treatment) of a large cohort of participants with ADHD-combined type (N = 347, mean age 11.4 years) in late adolescence and early adulthood. At study entry and follow-up (mean age 17.4 years), participants were comprehensively assessed on ADHD and comorbid disorders by structured psychiatric interviews and multi-informant questionnaires. Overall functioning was assessed by the Children's Global Assessment Scale. The retention rate was 75.6 %. The majority of participants (86.5 %) persisted in a DSM-5 ADHD diagnosis, 8.4 % had a subthreshold diagnosis, and 5.1 % remitted from the disorder at follow-up. Comorbidities decreased strongly; oppositional defiant disorder: 58 > 31 %, conduct disorder: 19 > 7 %. At follow-up, mood- and anxiety disorders were virtually non-existent following strict criteria (1-3 %). Percentage of children having had pharmacological treatment at any time increased from 79 to 91 %. On the Children's Global Assessment Scale, 48.5 % of participants were still functionally impaired at follow-up. Parental ADHD, higher ADHD symptom severity at baseline and higher parent-reported impairment at baseline positively predicted current ADHD symptom severity (R (2) = 20.9 %). Younger baseline age, higher ADHD symptom severity at baseline and higher parent-reported impairment at baseline were positively associated with poorer overall functioning (R (2) = 17.8 %). Pharmacological treatment had no (beneficial) impact on either ADHD symptom severity or overall functioning. Results confirm that ADHD is largely persistent into late adolescence with severity and family history for the disorder as important risk factors.

How 'core' are motor timing difficulties in ADHD? A latent class comparison of pure and comorbid ADHD classes.

Children with attention-deficit/hyperactivity disorder (ADHD) have motor timing difficulties. This study examined whether affected motor timing accuracy and variability are specific for ADHD, or that comorbidity with autism spectrum disorders (ASD) contributes to these motor timing difficulties. An 80-trial motor timing task measuring accuracy (µ), variability (σ) and infrequent long response times (τ) in estimating a 1-s interval was administered to 283 children and adolescents (8-17 years) from both a clinic and population based sample. They were divided into four latent classes based on the SCQ and CPRS-R: L data. These classes were: without behavioral problems 'Normal-class' (n = 154), with only ADHD symptoms 'ADHD-class' (n = 49), and two classes with both ASD and ADHD symptoms; ADHD(+ASD)-class (n = 39) and ASD(+ADHD)-class (n = 41). The pure ADHD-class did not deviate from the Normal class on any of the motor timing measures (mean RTs 916 and 925 ms, respectively). The comorbid ADHD(+ASD) and ASD(+ADHD) classes were significantly less accurate (more time underestimations) compared to the Normal class (mean RTs 847 and 870 ms, respectively). Variability in motor timing was reduced in the younger children in the ADHD(+ASD) class, which may reflect a tendency to rush the tedious task. Only patients with more severe behavioral symptoms show motor timing deficiencies. This cannot merely be explained by high ADHD severity with ASD playing no role, as ADHD symptom severity in the pure ADHD-class and the ASD(+ADHD) class was highly similar, with the former class showing no motor timing deficits.

Distinguishing Adolescents With ADHD From Their Unaffected Siblings and Healthy Comparison Subjects by Neural Activation Patterns During Response Inhibition.

OBJECTIVE: Dysfunctional response inhibition is a key executive function impairment in attention deficit hyperactivity disorder (ADHD). Still, behavioral response inhibition measures do not consistently differentiate affected from unaffected individuals. The authors therefore investigated neural correlates of response inhibition and the familial nature of these neural correlates. METHODS: Functional MRI measurements of neural activation during the stop-signal task and behavioral measures of response inhibition were obtained in adolescents and young adults with ADHD (N=185), their unaffected siblings (N=111), and healthy comparison subjects (N=124). RESULTS: Stop-signal task reaction times were longer and error rates were higher in participants with ADHD, but not in their unaffected siblings, while reaction time variability was higher in both groups than in comparison subjects. Relative to comparison subjects, participants with ADHD and unaffected siblings had neural hypoactivation in frontal-striatal and frontal-parietal networks, whereby activation in inferior frontal and temporal/parietal nodes in unaffected siblings was intermediate between levels of participants with ADHD and comparison subjects. Furthermore, neural activation in inferior frontal nodes correlated with stop-signal reaction times, and activation in both inferior frontal and temporal/parietal nodes correlated with ADHD severity. CONCLUSIONS: Neural activation alterations in ADHD are more robust than behavioral response inhibition deficits and explain variance in response inhibition and ADHD severity. Although only affected participants with ADHD have deficient response inhibition, hypoactivation in inferior frontal and temporal-parietal nodes in unaffected siblings supports the familial nature of the underlying neural process. Activation deficits in these nodes may be useful as endophenotypes that extend beyond the affected individuals in the family.

The role of age in association analyses of ADHD and related neurocognitive functioning: A proof of concept for dopaminergic and serotonergic genes.

Elucidating genetic mechanisms involved in Attention-Deficit/Hyperactivity Disorder (ADHD) has been challenging. Relatively unexplored is the fact that genetic mechanisms can differ with age. The current study explored the association between dopaminergic and serotonergic genes, ADHD symptoms, and neurocognitive functioning in relation to age. Associations of three genetic ADHD risk factors, DAT1, DRD4, and 5-HTT with symptoms and six neurocognitive measures were explored in two samples of the NeuroIMAGE study: 756 children, adolescents, and young adults with ADHD, their siblings, and controls (M age 17 years, SD 3.2), and 393 parents with and without ADHD (M age 48 years, SD 4.8). Association analyses were performed in both samples, and effects were compared to address dichotomous age effects. Gene*age interactions were examined to address continuous age effects. Moderating effects of age were found for DRD4-7R carriership and ADHD symptoms in the adult group only; in the adolescents the 5-HTT LL genotype was differentially associated with inhibition and with motor timing at different ages, and to inhibition in adults; DAT1 10-6 haplotype carriership showed differential working memory performance depending on age. None of our effects survived correction for multiple comparisons. Our results are preliminary, but may point to differential genotype-phenotype associations at different ages. This can be seen as a proof of concept for the importance of age in dopaminergic and serotonergic genetic association analyses. Our findings are consistent with the idea that genetic and neurocognitive mechanisms underlying ADHD may change throughout life. © 2015 Wiley Periodicals, Inc.

Attention-deficit/hyperactivity disorder (ADHD) and motor timing in adolescents and their parents: familial characteristics of reaction time variability vary with age.

OBJECTIVE: There is consistent evidence that attention-deficit/hyperactivity disorder (ADHD) is strongly related to impaired motor timing as reflected in decreased accuracy and increased reaction time variability (RTV). It is not known whether motor timing impairments are present in adolescents and adults with ADHD and their unaffected relatives to the same extent as has been reported in children, and whether ADHD and motor timing share familial underpinnings, as reflected in parent-offspring co-segregation and sibling cross-correlations. METHOD: A total of 589 parents and 808 children/adolescents from families with ADHD and control families (parent/offspring average age: 48.6/17.3 years) were included. All participants were thoroughly assessed for ADHD and performed a 40-trial motor timing task (1-second interval production). Dependent neurocognitive measures included RT median (RTM: representing accuracy), RTV and ex-Gaussian component τ (τ: representing infrequent long response times). Generalized estimating equations were used for analyses. RESULTS: Unaffected children from families with ADHD had RTV (but not RTM or τ) scores in between those of affected and control children. However, during middle-to-late adolescence, unaffected offspring were not impaired compared to control offspring and differed from ADHD probands, whereas during late adolescence/early adulthood, all offspring groups performed equally. Affected and unaffected parents of families with ADHD showed increased RTV compared to controls, regardless of age (not significant after adjusting for IQ). There were indications for shared familiality between RTV and ADHD as reflected by sibling cross-correlations and between RTM and ADHD as reflected by sibling cross-correlations and a maternal parent-offspring relation (parent-of-origin effect). CONCLUSIONS: RTV and its familial characteristics are influenced by development during adolescence. Increased RTV in children with ADHD appears to reflect immaturities in their neurocognitive functioning. Maternal ADHD effects might be involved in transmission of RTM (not RTV), but overall RTM showed less compelling (familial) relationships with ADHD than RTV.

Parent-of-origin effects in ADHD: distinct influences of paternal and maternal ADHD on neuropsychological functioning in offspring.

OBJECTIVE: The authors examined parent-of-origin effects in transmission of ADHD and neuropsychological functioning. Proof of these effects can identify more etiologically homogeneous ADHD subgroups and facilitate genetic studies. METHOD: The authors included 238 ADHD and 147 control families. ADHD in children was assessed using parent and teacher ratings, while parents completed self-reports. Children were assessed with neuropsychological paradigms measuring IQ, motor, timing, and executive functions. RESULTS: Paternal and maternal ADHD were equally positively related to ADHD in offspring. Paternal ADHD was related to poorer time reproduction in offspring and to lower verbal and total IQ in daughters. Maternal ADHD was related to poorer inhibition and motor control in offspring. No mediating effects of neuropsychological functions were found between parent and offspring ADHD symptoms. CONCLUSION: Neuropsychological functions may be more sensitive to parent-of-origin effects than ADHD symptoms and possibly useful in detecting the transmission of different gene-brain network pathways depending on parental sex.